Phenthiazine derivatives

ABSTRACT

Phenthiazine derivatives of the formula:   WHEREIN R represents an alkyl, alkyenyl or alkynyl group having at least 4 carbon atoms, are very active as long-acting neuroleptics, anti-emetics and tranquilisers.

United States Patent [191 Blondel et al.

[11] 3,875,156 [4 1 Apr. 1, 1975 I PHENTHIAZINE DERIVATIVES [75]Inventors: Jean-Claude Rene Georges Blondel,

' Essonne; Jean Clement Louis Fouche, Hauts-De-Seine; Claude GeorgesAlexandre Gueremy, Val-de-Marne, all of France [73] Assignee:Rhone-Ponlenc S.A., Paris, France [22] Filed: Mar. 28, 1968 [21] Appl.No.: 717,012

[30] Foreign Application Priority Data FOREIGN PATENTS OR APPLICATIONS904.208 1962 United Kingdom 260/243 Primary E.raminerHarry I. MoatzAttorney, Agent, or Firm-Stevens, Davis, Miller & Mosher [57] ABSTRACTPhenthiazine derivatives of the formula:

(CH2) -10- (CH2) -o-co-n wherein R represents an alkyl, alkyenyl oralkynyl group having at least 4 carbon atoms, are very active aslong-acting neuroleptics, anti-emetics and tranquilisers.

5 Claims, No Drawings PHENTHIAZINE DERIVATIVES This invention relates tonew therapeutically useful phenthiazine derivatives, to processes fortheir preparation and pharmaceutical compositions containing them.

According to the present invention, there are provided the newphenthiazine derivatives of the general formula:

\ I so MCI-l l i 2 2 I (CH2)3- N (CH2)2-0-CO-R wherein R represents astraight or branched alkyl, alkenyl or alkynyl group containing at least4 carbon atoms, and preferably not more than 17 carbon atoms, forexample butyl, t-butyl, pentyl, hexyl, l-ethylpentyl, lmethylhexyl,heptyl, 1,1-dimethylhexyl, octyl, nonyl, non-l-enyl, dec-9-enyl,dec-9-ynyl, decyl, undecyl, tridecyl, pentadecyl or heptadecyl, and acidaddition salts thereof. When the group R contains a multiple bondbetween carbon atoms. the multiple bond may be located in any positionof the hydrocarbon chain.

According to a feature of the present invention, the phenthiazinederivatives of formula I are prepared by the process which comprisesreacting 3- dimethylsulphamoyl-lO---[4-(2-hydroxyethyl)piperidino]propyl}phenthiazine of the formula:

II so mcrg) with a compound of the general formula RCO-X, wherein R isas hereinbefore defined and X represents the acid residue of a reactiveester, for example a halogen atom. the hydroxy group, an alkoxy groupcontaining from 1 to 4 carbon atoms, an imidazolyl group, or analkanoyloxy, alkenoyloxy or alkynoyloxy group which may have a straightor branched hydrocarbon chain, and may. more particularly, be such thatthe compound RCO-X represents the acid anhydride of formula RCOOCOR, Rbeing as hereinbefore defined.

When the symbol X represents a halogen atom, in particular chlorine. oran imidazolyl, alkanoyloxy, alkenoyloxy or alkynoyloxy group, it isadvantageous to carry out the process in an inert organic solvent (forexample benzene, toluene or chloroform), and preferably at the boilingpoint of the solvent employed in the absence or presence of an inorganicor organic acidbinding agent.

When the symbol X represents the hydroxy group, the process is generallycarried out in an inert organic solvent in the presence of either astrong acid or a Lewis acid or of dicyclohexylcarbodiimide.

When the symbol X represents an alkoxy group, the process is generallycarried out in an inert organic solvent such as toluene and the alcoholformed is removed by azeotropic distillation.

According to a further feature of the invention, the phenthiazinederivatives of formula I are prepared by the process which comprisesreacting a phenthiazine of the formula:

N III wherein Y represents the acid residue of a reactive ester such asa halogen atom or a sulphuric or sulphonic ester residue (for example amethanesulphonyloxy or toluene-p-sulphonyloxy residue) with an alkalimetal salt of an acid of the formula RCOOH (wherein R is as hereinbeforedefined), the process being carried out in an inert organic solvent andpreferably at the boiling point of the solvent employed.

The alcohol of formula ll may be prepared, for example, by applicationof the processes described in the specification of British Pat. No.904208 with the title New Phenthiazine derivativs and processes fortheir preparation granted to Rhone-Poulenc SA. on an application filedOct. 16th, 1959.

The phenthiazine compounds of general formula 111 may be prepared fromthe alcohol of formula ll by applying any process which is known per sefor replacing a hydroxy group by a reactive ester residue, such as Ydefined above.

The phenthiazine derivatives of formula I obtained according to theforegoing processes may be purified by physical methods such asdistillation, crystallisation or chromatography, or by chemical methodssuch as the formation of salts, crystallisation of the salts anddecomposition of them in an alkaline medium. In the said chemicalmethods, the nature of the anion of the salt is immaterial, the onlyrequirement being that the salt must be well-defined and readilycrystallisable.

The phenthiazine derivative of formula I may be converted in mannerknown per se into acid addition salts. The acid addition salts may beobtained by the action of acids on the new phenthiazine derivatives inappropriate solvents. As organic solvents there may be used, forexample, alcohols, ethers, ketones or chlorinated hydrocarbons. The saltwhich is formed is precipitated, if necessary after concentration of itssolution, and is separated by filtration or decantation.

The phenthiazine derivatives of the present invention have interestingpharmacodynamic properties; they are very active as long-actingneuroleptics, anti-emetics and tranquillisers. They have given goodresults as such in physiological experiments with animals at doses of0.005 to 1.0 mg./kg. of animal weight by subcutaneous or intramuscularadministration. For example, the compounds of formula I have been foundto have a prolonged antagonistic effect against emesis caused byapomorphine in the dog. A subcutaneous dosage of one of the newcompounds (as the free base) of 0.05 to 0.8

so mcn mg./kg. reduces the number of vomits caused by subcutaneousadministration of 0.1 mg./kg. of apomorphine by 50% for from 10 to 50days. The compounds of formula I have shown no toxic effects at dosagesas least as high as 0.8 mg./kg. Preferred compounds are 3-dimethylsulphamoyl-l-{3-l4-(2-palmitoyloxyethyl)- piperidino]propylphenthiazine, 3- dimethylsulphamoyl-l0-{3[4-(2-undec-10'-enoyloxyethyl)piperidinolpropyl}phenthiazine and 3-dimethylsulphamoyl-l0-{3-[4-(2- lauroyloxyethyl)piperidino]propyl}phenthiazine.

The following Examples illustrate the invention.

EXAMPLE I 3-Dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)piperidino]propyl -phenthiazine (9.5 g.), palmitoylchloride (5.5 g.) and anhydrous toluene (165 cc.) are heated underreflux for 5 hours. After cooling, the reaction mixture is stirred forminutes in the presence of distilled water (200 cc.) and an aqueous 10%solution of sodium carbonate (50 cc.). The decanted organic solution iswashed three times with distilled water (total 600 cc.) until neutral,dried over anhydrous magnesium sulphate and evaporated under reducedpressure mm.Hg). The residue (14.9 g.), dissolved in acetone (50 cc.)under reflux, is treated with anhydrous oxalic acid (1.9 g.) dissolvedin acetone (10 cc.). After 17 hours cooling at 3C, the crystals whichhave appeared are filtered off, washed twice with ice-cooled acetone(total 50 cc.) and dried under reduced pressure (20 mm.Hg). 3-Dimethylsulphamoyl-IO-{3-[4-(2-palmitoyloxyethyl)piperidino]-propyl}phenthiazine oxalate (15.2 g.),melting at about 134C, is obtained.

The palmitoyl chloride (b.p. 157-166C/O.2 mm.Hg) is prepared accordingto W. G. Rose, J. Am. Chem. Soc., 69, 1384 (1947).

3-Dimethylsulphamoyl-l0-{3-[4-(2- hydroxyethyl)piperidino]propyl-phenthiazine employed as starting material is prepared by the proceduredescribed in the specification of British Pat. No. 904208 by reacting4-(2-hydroxyethyl)piperidine with3-dimethylsulphamoyl-10-(3-hydroxypropyl)phenthiazine methanesulphonate.

EXAMPLE II By following the procedure described in Example 1 butstarting with 3-dimethylsulpharnoyl-10-{3-[4-(2-hydroxyethyl)piperidino]propyl phenthiazine (9.5 g.), undec-lO-enoylchloride (4.05 g.) and toluene (165 cc.),3-dimethylsulphamoyl-10-{3-[4(2-undecl0'-enoyloxyethyl)piperidino1propyl}phenthiazineoxalate (12.8 g.), melting at about 126C, is obtained.

Undec-lO-enoyl chloride employed as starting material (b.p. 74-75C/0.2mm.Hg) is prepared according to J. English et coll, J. Am. Chem. Soc.,67, 1413, (1945).

EXAMPLE 111 By following the procedure described in Example 1 butstarting with 3-dimethylsulphamoy110-{3-[4-(2-hydroxyethyl)piperidino]-propyl phenthiazine (9.5 g.), lauroyl chloride(4.40 g.) and toluene (165 cc.). 3-dimethylsulphamoyl-l0-{3-[4-(2-lauroyloxyethyl)piperidinol-propyl phenthiazine oxalate (13.1 g.),melting at about 130C, is obtained.

Lauroyl chloride employed as starting material (b.p. C/2 mm. Hg) isprepared according to H. Richet, Bull. Soc. Chim. Fr., (1946), 52.

EXAMPLE IV By following the procedure described in Example 1 butstarting with 3-dimethylsulphamoyl-l0- 3-[4-(2-hydroxyethyl)piperidino]-propyl phenthiazine (4.75 g.), decanoylchloride (2.11 g.) and toluene (110 cc.),3-dimethylsulphamoyl-10-{3-[4-(2-decanoyloxyethyl)- piperidino]propyl}phenthiazine oxalate (6.20 g.), melting at about 134C, is obtained.

Decanoyl chloride employed as starting material (b.p. 100-102C/10 mm.Hg)is prepared according to J. Cason et coll, J. Org. Chem. 26, 1768,(1961).

EXAMPLE V By following the procedure described in Example 1 but startingwith 3-dimethylsulphamoyll0-{3-[4-(2- hydroxyethyl)-piperidino]propylphenthiazine (6.8 g.), heptanoyl chloride (2.4 g.) and toluene cc.),3-dimethylsulphamoy1-10-{3-[4-(2-heptanoyloxyethyl)piperidino]propyl}phenthiazine oxalate (2.12 g.),melting at about C, is obtained.

Heptanoyl chloride employed as starting material (b.p. 87-88C/25 mm.Hg)is prepared according to M.'

Sulzbacher et coll, J. Org. Chem., 13, 303, (1948).

EXAMPLE V1 EXAMPLE VII By following the procedure described in Example 1but starting with 3-dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)piperidino]propyl -phenthiazine (9.5 g.),2,2-dimethylheptanoyl chloride (3.53 g.) and toluene (165 cc.),3-dimethylsulphamoyl-10-{3-[4-(2-2',2-dirnethylheptanoyloxyethyl)piperidino]propylphenthiazine oxalate(13.1 g.), melting at about C, is obtained.

2,2-Dimethylheptanoyl chloride employed as starting material (b.p.71.5C/10 mm.Hg) is prepared according to M. Nuraya, Chein. Pharm. Bull.(Tokyo), 6, 186, (1958).

EXAMPLE VIII By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)-piperidino]propyl phenthiazine (4.75 g.), Z-ethylhexanoylchloride (1.8 g.) and toluene (100 cc.),3-dimethylsulphamoyl-10-{3-[4-(2-2'-ethylhexanoyloxy-ethyl)piperidino]propyl}phenthiazine oxalate (6.1 g.),melting at about 166C, is obtained.

2-Ethylhexanoyl chloride employed as starting material (b.p. 7l72C/20mm.Hg) is prepared according to E. H. Man et coll, J. Am. Chem. Soc.,73, 901 (1951).

EXAMPLE IX EXAMPLE X By following the procedure described in Example Ibut starting with 3-dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)piperidino]-propyl phenthiazine (4.75 g.), octanoylchloride (1.76 g.) and toluene (110 cc.),3-dimethylsulphamoyl10{3-[4-(2-oxtanoy1oxyethyl) piperidino]propylphenthiazine oxalate (5.95 g.), melting at about 148C, is obtained.

Octanoyl chloride employed as starting material (b.p. 9697C/25 mm.Hg) isprepared according to J. Cason, J. Org. Chem. 23, 1492, (1958).

EXAMPLE XI By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)piperidinol-propyl phenthiozine (4.75 g.) and Valerylchloride (1.35 g.) in toluene (110 cc.), 3-dimethylsulphamoyl-l0{3l4(2-valeryloxyethyl)piperidino]-propy1} phenthiazine oxa late (4.2 g.),melting at about 136C, is obtained.

Valeryl chloride employed as starting material is prepared according toH. C. Brown et coll, J. Am. Chem. Soc., 60. 1325, (1938).

EXAMPLE XII By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)piperidino]propyl -phenthiazine (4.75 g.) and pivaloylchloride (1.33 g.) in toluene (l cc.), 3-dimethylsulphamoyl-10-{3-[4-(2-pivaloyloxyethyl)piperidino]-propy1}phenthiazine oxalate (4.7 g.),melting at about 156C, is obtained.

Pivaloyl chloride employed as starting material is prepared according toJ. G. Traynham et coll, J. Org. Chem.,22. 1551. (1957).

EXAMPLE XIII By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)piperidino]-propy1 phenthiazine (4.75 g.) and undecanoylchloride (2.3 g.) in toluene (100 cc.),3-dimethylsulphamoyl-l0-{3-[4-(2-undecanoyloxyetliyl)piperidino]propyl}phenthiazine oxalate (6.2 g).melting at about 130C, is obtained.

Undecanoyl chloride employed as starting material is prepared accordingto H. E. Fierz-David and W. Kuster, Helv. Chim. Acta, 22, 89 (1939).

EXAMPLE XIV By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-10- 3-[4-(2-hydroxyethyl)piperidino]-propyl}phenthiazine (4.7 g.) and nonanoylchloride (195 g.) in toluene cc.), 3-dimethylsulphamoyll 0- {3-[4-( 2-nonanoyloxyethyl)piperidino]propy1 }phenthiazine oxalate (2.95 g.),melting at about C., is obtained.

Nonanoyl chloride employed as starting material is prepared according toH. E. Fierz-David and W. Kuster, Helv. Chim. Acta, 22, 89 (1939).

EXAMPLE XV By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-10{3-[4-(2-hydroxyethyl)piperidino]-propyl phenthiazine (4.75 g.) andundec-l0-ynoyl chloride (2.2 g.) in toluene (100 cc.),3-dimethylsulphamoyl-lO-{3-[4-(2-undecl0'-ynoyloxyethyl)piperidino]propyl}phenthiazineoxalate (5 g.), melting at about 133C., is obtained.

Undec-lO-ynoyl chloride is prepared according to L. D. Bergelson etc011, Zh. obshch, Khim., 32, 58 (1962); Chem. Abstr., 57, 14930 b(1962).

EXAMPLE XVI By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-lO-{3-[4-(2-hydroxyethyl)piperidino]-propyl phenthiazine (4.75 g.) and myristoylchloride (3.7 g.) in toluene (100 cc.),3-dimethylsulphamoyl-10-{3-[4-(2- myristoyloxyethyl)piperidinolpropyl}phenthiazine oxalate (6.3 g.), melting at about 134C, is obtained.

Myristoyl chloride employed as starting material is prepared accordingto H. E. Fierz-David and W. Kuster, Helv. Chim. Acta, 22, 89 (1939).

EXAMPLE XVII 3-Dimethylsulphamoyl-l0- {3-[4-(2-hydroxyethyl)piperidino]-propyl phenthiazine (4.75 g.) is reacted withstearoyl chloride (3.34 g.) in toluene (100 cc.) according to theprocedure described in Example I. After washing and evaporating thesolvent, the resulting base is recrystallised from ethanol to give 3-dimethylsulphamoyl-l0{3-[4(2-stearoyloxyethyl)piperidino]propyl}-phenthiazine (5.9 g.), melting atabout 62C.

Stearoyl chloride employed as starting material is prepared according toH. E. Fierz-David and W. Kuster, Helv. Chim. Acta, 22, 89 (1939).

EXAMPLE XVIII By following the procedure described in Example I butstarting with 3-dimethylsulphamoyl-10-{3-[4-(2-hydroxyethyl)piperidino]-propyl}phenthiazine (9.5 g.) and dec-2-enoylchloride (4.14 g.) in toluene (200 cc.), 3-dimethy1sulphamoyl-lO-3-[4-(2-dec-2'- enoyloxyethyl)piperidino]propyl }phenthiazine oxalate(6.8 g.), melting at about 138C, is obtained.

Dec-2-enoyl chloride employed as starting material is prepared accordingto P. Van Romburgh, Rec. Trav. Chim. Pays-Bas, 57, 494 (1938).

EXAMPLE XIX 3-Dimethylsulphamoyl-10- {3-[4-(2-undec-l0'-enoyloxyethyl)-piperidino]propyl phenthiazine oxalate (308 g.), preparedas described in Example 11, is

suspended in distilled water (2 litres) and methylene chloride (1litre). A aqueous solution of sodium bicarbonate (1.250 litres) is addedand the mixture is stirred for 5 minutes. After decantation of theorganic phase, the aqueous phase is extracted twice with methylenechloride (total 1 litre). The organic phases are combined, washed 3times with distilled water (total 1.5 litres) and dried over anhydroussodium sulphate. After filtration, the solvent is removed by heatinginitially at 60C. under ordinary pressure and then at 100C. underreduced pressure mm. Hg.). The crude oily base obtained (274 g.) ispurified by chromatography through a column of neutral alumina (1 kg.)and elution with benzene (total 5.5 litres).

The benzene is then evaporated under reduced pressure (20 mm. Hg) toyield the purified base (240 g.), which is dissolved at 60C. incyclohexane (650 cc.). After cooling to 40C., petroleum ether (b.p.40-65C., 1,350 cc.) is added. The mixture is cooled to 29C.,crystallisation of the product initiated, and

then it is left for 2 hours at 20C. and overnight at 3C. The crystalswhich form are filtered off, washed twice with iced petroleum ether (300cc. total) and dried under reduced pressure (20 mm. Hg.) to yield 3-dimethylsulphamoyl-10-{3-[4-(2-undec-l0-enoyloxyethyl)piperidino]-propyl }phenthiazine melting at 58-59C.

The present invention includes within its scope pharmaceuticalcompositions containing, as active ingredient, at least one of thephenthiazine derivatives of formula l in association with apharmaceutical carrier or coating. The invention includes especiallysuch preparations made up for parenteral, in particular intramuscular orsubcutaneous, administration.

Preparations for parenteral administration include sterile non-aqueoussolutions. Examples of suitable non-aqueous solvents are injectablevegetable oils, such as sesame oil or olive oil, and injectable organicesters such as ethyl oleate. The preparations may be sterilised by, forexample, filtration through a bacteriaretaining filter, by incorporationin the compositions of sterilising agents, by irradiation, or byheating.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. The dosage depends on thedesired therapeutic effect and on the duration of the treatment. Inhuman therapy the compositions should generally be administered so as togive to an adult between 5 mg. and 100 mg. of active substance at therate of one intramuscular injection every 2 to 4 weeks.

Because of the prolonged anti-emetic effect of the new phenthiazinederivatives mentioned above, it is often desirable to administer thecompounds by intramuscular or subcutaneous injection as depotpreparations. Such preparations may be made by conventional methods,e.g. by dissolving the new bases of formula l in an injectablewater-insoluble vegetable oil, e.g. in a concentration of 0.25 to 10% byweight, and, if necessary, subsequently sterilizing the solutionobtained by filtration through a bacteriological filter.

The following Examples illustrate the preparation of pharmaceuticalcompositions according to the invention.

EXAMPLE XX 3-Dimethylsulphamoyl-10-{3-[4-(2-lauroyloxyethyl)piperidino]-propyl }phenthiazine oxalate (170 mg.) istreated at ambient temperature with a mixture of a 1% aqueous solutionof sodium bicarbonate (l 10 cc.) and diethyl ether (50 cc.). Afterdissolution, the ethereal phase is decanted, washed with distilled water(2 X 50 cc.) until neutral, and then dried over anhydrous magnesiumsulphate. After concentration under reduced pressure (20 mm.Hg). theresidue (150 mg.) is dissolved in sesame oil (15 cc.) at 40C. Aftercooling to ambient temperature, a clear yellow solution containing 1% of3-dimethylsulpham0yl-l0{3-[4-(2-lauroyloxyethyl)piperidino]propyl}phenthiazine is obtained.

EXAMPLE XXl 3-Dimethylsulphamoyl-10-{3-[4-(2-undec-l0-enoyloxyethyl)-piperidino]propyl phenthiazine (2.5 g.) is dissolved at40C. in neutralised sesame oil cc.) with agitation. After cooling, theyellow solution obtained is filtered through a bacteriological filterunder a nitrogen pressure of 2 kg./cm The filtered solution is thenaseptically distributed into 5 cc. ampoules giving 4.1 cc. of solutionper ampoule. The filled ampoules are sealed under nitrogen.

The resulting ampoules each contain 100 mg. of active product ready forintramuscular administration.

EXAMPLE XXII By proceeding as described in Example XXI but using3-dimethylsulphamoyl-l0-{3-[4-palmitoyloxyethyl)piperidino]propyl}-phenthiazine, m.p. 6162C., ampoulesare obtained each containing 100 mg. of active product.

We claim:

1. A phenthiazine derivative of the formula:

wherein R represents an alkyl, alkenyl or alkynyl group having 7-17carbon atoms.

2. A phenthiazine derivative according to claim 1 wherein R representsl-ethylpentyl, l-methylhexyl, heptyl, 1,1-dimethylhexyl, octyl, nonyl,non-l-enyl, dec-9-enyl, dec-9-ynyl, decyl, undecyl. tridecyl, pentadecylor heptadecyl.

3. 3-Dimethylsulphamoyl-l0-{3-[4-(2-palmitoyloxyethyl)-piperidino]propyl}phenthiazine.

4. 3-Dimethylsulphamoyl-10-{3-[4-(2-undecl0-enoyloxyethyl)piperidino]propyl}phenthiazine.

5. 3-Dimethylsulphamoyl-l0-{3-[4-(2-lauroyloxyethyl)-piperidino]propyl}phenthiazine.

1. A PHENTHIAZINE DERIVATIVE OF THE FORMULA:
 2. A phenthiazinederivative according to claim 1 wherein R represents 1-ethylpentyl,1-methylhexyl, heptyl, 1,1-dimethylhexyl, octyl, nonyl, non-1-enyl,dec-9-enyl, dec-9-ynyl, decyl, undecyl, tridecyl, pentadecyl orheptadecyl.
 3. 3-Dimethylsulphamoyl-10-(3-(4-(2-palmitoyloxyethyl)-piperidino)propyl)phenthiazine. 4.3-Dimethylsulphamoyl-10-(3-(4-(2-undec-10''-enoyloxyethyl)piperidino)propyl)phenthiazine. 5.3-Dimethylsulphamoyl-10-(3-(4-(2-lauroyloxyethyl)-piperidino)propyl)phenthiazine.